Methods for making tablets and other solid or dry pharmaceutical preparations are well-known. For example in the well-known English language text Chase, et al, Remington's Pharmaceutical Sciences, pp. 1553-1576 (16th ed. 1980, Mack Publ. Co. of Easton, Pa., U.S.A.) ("Remington's"), methods of making tablets, capsules and pills and their respective components are described.
Three methods of making tablets include the "wet-granulation", "dry-granulation", and direct compression methods.
Wet-granulation methods involve weighing out ingredients (including a solvent), mixing the ingredients, granulating them, screening them damp, drying them, dry screening, lubrication, and compressing the resultant admixture into tablets. See, e.g. Belgian Patent No. 773,064. Such procedures result in tablets having at least adequate tablet homogeneity. Wet-granulation methods may have a disadvantage when certain solvents, which may not be desired in view of environmental and safety concerns, are used.
The dry methods (dry-granulation and direct compression) are especially suitable for medicinal compounds which are sensitive to moisture or are unable to withstand the elevated drying temperatures associated with wet-granulation methods.
Dry granulation methods involve fewer steps (i.e. weighing, mixing, slugging, dry screening, lubrication and compression), while direct compression methods lack the slugging and, usually, the dry screening steps. However, these dry methods have heretofore not been entirely successful in providing optimal tablet homogeneity when used with certain very potent medicinal compounds. For example, compounds such as certain extremely potent steroids require only very low doses of the compound per tablet (e.g. &lt;1.0 milligrams (mg)/100 mg tablet) and do not always distribute entirely evenly throughout a tableting mixture possibly resulting in some tablets having relatively high amounts of steroid (i.e. "superpotent tablets"), while others have very low amounts of steroid or possibly none at all.
A common diluent used with both wet and dry granulating processes is lactose. Different types or lactose are commercially available. There are .alpha.-lactose monohydrate, .beta.-lactose (also known as "anhydrous lactose DT", and used in direct compression methods), anhydrous lactose, and spray-dried lactose (see, e.g. Martindales' The Extra Pharmacopoeia, p. 54 (The Pharmaceutical Press, London 28th ed. 1982).
Certain types of lactose have been used with low dose steroids to make tablets. For example in U.S. Pat. No. 4,628,051 to Pasquale, compositions containing anhydrous lactose DT (i.e. .beta.-lactose) and low dose steroids are disclosed. The disclosed compositions when used in a dry procedure produce tablets of inadequate homogeneity (see e.g. EXAMPLE II, infra). Similar compositions are disclosed in U.S. Pat. Nos. 4,544,554, 4,616,006, and 4,530,839 also to Pasquale
Other tablet compositions containing lactose and a low dose steroid are described in the art. However, by including polyvinylpyrrolidone ("PVP"), stearic acid, or other ingredients exclusively used in wet-granulation processes in the formula for the preparations, one of skill in the art can readily determine that a wet-granulation procedure was used in forming the tablets. Such compositions are disclosed in U.S. Pat. Nos. 3,939,264, 3,969,502, and 3,957,982 to Lachnit-Fixson, U.S. Pat. No. 4,425,339 to Pitchford, U.S. Pat. No. 4,390,531 to Edgren, U.S. Pat. No. 3,822,355 to Biological Concepts, Inc., U.S. Pat. Nos. 4,378,356 and 4,143,136 to De Jager et al (stearic acid).
U.S. Pat. No. 3,671,633 to Sheth discloses a process of making acetazolamide tablets which does not require prior granulation or slugging to obtain commercially acceptable tablets. The process uses crystalline acetazolamide having a binodal size distribution mixed with, for example, 30 to 80 weight percent spray-dried lactose. Dosages of acetazolamide are typically 500 milligrams per tablet, so none of the problems associated with extremely potent drugs are encountered.
U.S. Pat. No. 4,916,163 to Ni discloses formulations of the non-steroid sulfonylurea glyburide having improved bioavailability consisting preponderantly (&gt;70%) of spray-dried lactose with a relatively narrow sieve fraction. Tablets disclosed contain micronized glyburide having a surface area of at least 3 m.sup.2 /g.
Tablet compositions containing steroids in combination with spray-dried lactose are also disclosed. For example U.S. Pat. No. 3,568,828 to Werner discloses oral contraceptive tablets made by mixing mestranol and chlormadinone in chloroform, adding microcrystalline cellulose to the solution, drying the mixture, and then blending the dried mixture with spray-dried lactose before compressing the blend into tablets. Although the mestranol and chlormadinone may be evenly distributed on the cellulose, the procedure still utilizes chloroform which is undesirable from environmental and safety view points.
U.S. Pat. No. 3,423,507 describes dry pharmaceutical formulations containing between 1.5 and 12.5 percent steroid by weight. In the preparation of the tablet formulations, the steroid is first mixed with an equal amount of starch, before blending with spray dried lactose. However as shown in EXAMPLE IV, infra, premixing a starch with an ultra-low dose steroid before blending with the spray-dried polyalcohol (SAMPLE 2) results in a dry mix having significantly lower content uniformity than mixtures wherein the steroid is first mixed with the spray-dried polyalcohol.
Compositions containing microdose quantities of a micronized model drug (salicylic acid, due to it low aqueous solubility and its hydrophobicity) and spray-dried lactose have been further used in wet granulation techniques to produce tablets having good homogeneity. Thiel et al, "Content uniformity of microdose tablets (dosage 1 .mu.g-10 mg) produced by fluid bed granulation of interactive mixtures", J. Pharm. Pharmacol, 38: 335-343 (1986); Thiel and Nguyen, "Fluidized bed granulation of an ordered powder mixture", J. Pharm. Pharmacol., 34: 692-699 (1982); and Thiel et al "Fluidised bed granulation of an Ordered Powder Mixture Reduces the Potential for Ordered Unit Segregation", Powder Technology, 34: 75-80 (1983). The demixing potential of the model drug when mixed with spray-dried lactose sans the application of a wet granulation technique was 70 to 80%. By the use of a wet granulation technique (5% aqueous solution of PVP) the demixing potential was reduced to 5.6 to 10.8%.